1. Field of the Invention
The invention relates to novel compounds useful for effecting vasodilation. More particularly, it relates to the use of novel (1,5-inter)aryl prostaglandin derivatives effective in stimulating vasodilation in warm-blooded animals.
2. Brief Description of the Art
Vasodilation is the dilation of vessels, generally resulting in increased blood flow to a part of the body. A wide variety of vasodilator drugs are known and have been used successfully in the treatment of pathophysiological diseases such as hypertension, angina pectoris, and congestive heart failure, to name a few. These agents may be classified according to their primary mechanism of action. One important group of vasodilators, which includes the nitrates and sodium nitroprusside-side, exert a direct effect on smooth muscle. Another important group of vasodilatory compounds, which includes captopril, enalapril and lislinopril, appear to exert their activity through the inhibition of enzymatic conversion of angiotensin I to angiotensin II, which is a potent constrictor of arteriolar resistance vessels. Alpha and beta-adrenoreceptor blocking agents and calcium antagonists have also been used successfully as vasodilators.
Despite reports of the development of pharmaceutical agents that lower blood pressure, improve congestive heart failure, or hasten recovery from anginal episodes, none of the vasodilator drugs currently available is ideal. A need continues to exist for medicaments that are useful in the treatment of these disorders, and especially for medicaments that not only exhibit a desirable pharmacological profile, but are also non-toxic, do not induce tachyphylaxis, and are inexpensive to manufacture. A need also exists for vasodilators that have a localized vasodilatory effect which can be used to counteract disorders associated with vasconstriction in localized or regional vascular beds.
Prostaglandin F.sub.2.alpha. has been reported to induce endothelium-dependent relaxation in isolated monkey cerebral arteries and in human hand veins. Despite its vasodilatory effects, the unwanted side effects associated with the systemic administration would preclude its use in such diseases as systemic hypertension, angina, and related disorders. Thus, PGF.sub.2.alpha. and its congeners contract most smooth muscles and this would lead to side effects that would include uterine contraction, diuresis, contraction of gastrointestinal smooth muscle bronchoconstriction, and vasoconstriction in many vascular beds resulting in an increase in systemic blood pressure. Thus, although PGF.sub.2.alpha. and its FP receptor agonist congeners such as fluprostenol may act as vasodilators, their potentially useful systemic effects are compromised and even reversed by smooth muscle contraction.
Our PGF.sub.2.alpha. structure-activity investigations revealed a most unexpected aspect of PGF.sub.2.alpha. (FP receptor) pharmacology. It was discovered that 1,5-interaryl PGF.sub.2.alpha. derivatives were selective for producing the vasodilation properties of PGF.sub.2.alpha.. Thus, these interphenylene PGF.sub.2.alpha. analogs described herein relaxed vascular smooth muscle but did not increase intracellular [Ca.sup.2+ ] in a PGF.sub.2.alpha. --sensitive preparation. Thus, such interphenylene PGF.sub.2.alpha. analogs would not contract smooth muscle since an increase in intracellular [Ca.sup.2+ ] is established as the trigger for contraction of vascular and other smooth muscles.
There are unique features associated with the vasodilatory mechanism of action of the interphenylene described herein. It has been demonstrated that their mechanism of action is vascular endothelium dependent and appears to involve release of nitric oxide. Although PGF.sub.2.alpha. and its structural analog fluprostenol also similarly relax this vascular smooth muscle preparation, they have not and could not be used for lowering blood pressure and/or increasing regional blood flow because of the unwanted side effects disclosed above. The interphenylene PGF.sub.2.alpha. analogs described herein could be used as vasodilators and would be the only class of drugs that could be used for increasing blood flow by a mechanism that involves release of NO from the vascular endothelium. An analogous situation exists for acetycholine and other cholinomimetics. They may also relax blood vessels by an identical mechanism but have not been used as vasodilator therapy since such a use would be injudicious as in the case of PGF.sub.2.alpha., due to their well-known smooth muscle contractile actions and other side effects.
Thus, in summary, it is an objective of the invention to provide (1,5-inter)aryl prostaglandin derivatives capable of stimulating vasodilation in warm-blooded animals that are non-toxic and suitable for pharmaceutical formulation and administration and lack certain side effects associated with prostaglandins such as PGF.sub.2.alpha..